Stable Antibody Containing Compositions

ABSTRACT

The invention relates to stable and low viscous (&lt;50 cP) protein containing compositions, in particular, but not exclusively stable antibody containing compositions and to the use of said stable proteins in therapy, in particular for the subcutaneous delivery of said stable protein.

FIELD OF THE INVENTION

The invention relates to stable and low viscous liquid compositionscontaining proteins, in particular, but not exclusively stableantibodies, and to the use of said compositions in therapy, inparticular for the subcutaneous delivery of said stable protein.

BACKGROUND OF THE INVENTION

Immunoglobulins, monoclonal antibodies (mAbs) and humanized antibodieshave been in development as pharmaceutical products for a number ofyears. There is a clear incentive for developing high concentrationliquid formulations of mAbs due to the potential of subcutaneousadministration which results in higher convenience for the patient.However, there is a general consensus that development ofhigh-concentration formulations of mAbs poses serious challenges withrespect to the physical and chemical stability of the mAb such asincreased formation of soluble as well as insoluble aggregates whichenhance the probability of an immunogenic response as well as give riseto low bioactivity.

Aggregate formation by a polypeptide during storage of a liquidpharmaceutical composition can adversely affect biological activity ofthat polypeptide, resulting in loss of therapeutic efficacy of thepharmaceutical composition. Furthermore, aggregate formation may causeother problems such as blockage of tubing, membranes, or pumps when thepolypeptide-containing pharmaceutical composition is administered usingan infusion system.

Furthermore, high-concentration formulations of mAbs have been reportedto result in increased viscosity thereby creating serious challenges forthe manufacturability and injectability.

Controlling aggregation and viscosity of liquid formulations ofhigh-concentration mAbs is not a trivial matter. The fact that only fewmAb product on the market exists as a high concentration liquidformulation 100 mg/ml) displays the complexity. Papers have beenpublished which show that NaCl may lower the viscosity and also to someextent control aggregation (EP 1981824). Sucrose has also shown tostabilise mAb against formation of aggregates by way of a preferentialexclusion mechanism. However, identifying suitable stabilisers is stillan empirical science in this field.

It is well known that relatively high amounts of electrolytes, such assalt and buffer, are used to lower the viscosity of high concentrationmAb formulations (EP 1981824). WO 01/24814 (Chiron Corporation)describes liquid polypeptide-containing pharmaceutical compositioncomprising an amino acid base as a stabiliser. EP 1336410 (ChugaiSeiyaku Kabushiki Kaisha) describes an injectable pharmaceuticalformulation containing a physiologically active protein and at least onesugar as a soothing agent. EP 1314437 (Chugai Seiyaku Kabushiki Kaisha)describes an antibody containing preparation comprising a glycine and/orhistidine buffer. WO 02/30463 (Genentech, Inc) describes a concentratedprotein formulation having reduced viscosity and a salt and/or buffer inan amount of at least about 50 mM. EP 1475100 (Chugai Seiyaku KabushikiKaisha) describes an antibody containing solution comprising an organicacid and a surfactant as stabilisers. EP 1475101 (Chugai SeiyakuKabushiki Kaisha) describes an antibody containing solution comprising asugar as a stabiliser. WO 2004/001007 (IDEC Pharmaceuticals Corporation)describes a concentrated antibody composition consisting essentially ofhistidine or acetate buffer in the range of from about 2 mM to about 48mM. WO 2004/016286 (Abbot Laboratories (Bermuda) Ltd.) describes aformulation of human antibodies having a pH of between about 4 and 8. WO2005/123131 (Medimmune Vaccines, Inc) describes a formulation for spraydrying an antibody or vaccine. WO 2007/003936 (Insense Limited)describes a stable aqueous system comprising a protein and one or morestabilising agents which have ionisable groups. WO 2007/092772(Medimmune, Inc.) describes a liquid protein formulation comprising anFc variant protein and between 1 mM to 100 mM buffering agent. US2004/0022792 (Immunex Corporation) describes a method of stabilising aprotein at a pH of between about 2.8 and about 4.0. US 2003/0180287(Immunex Corporation) describes an aqueous pharmaceutical compositionsuitable for long term storage of polypeptides. WO 2008/071394 (F.Hoffmann-La Roche AG) describes a stable pharmaceutical parenteralformulation containing an antibody. WO 2009/120684 and WO 2008/121615(MedImmune Inc) both describe high concentration liquid formulations ofantibodies or fragments thereof that specifically bind to a humaninterferon alpha polypeptide. WO 2009/070642 (MedImmune Inc) describesstable lyophilized formulations of bispecific antibodies or fragmentsthereof. EP 1 977 763 (Chugai Seiyaku Kabushiki Kaisha) describesantibody containing stabilising compositions comprising one or moreamino acids. US 2004/0197324 (Genentech, Inc) describes highlyconcentrated antibody and protein formulations with reduced viscosity.WO 2008/132439 (University of Strathclyde) describes precipitationstabilising compositions which are claimed to prevent or reduceaggregation. US 2007/0020255 (Kyowa Hakko Kogyo Co., Ltd) describes amethod of stabilising an antibody in solution which comprises theaddition of glycine and citric acid to the solution. US 2007/0184050(Kirin Beer Kabushiki Kaisha) describes a stable liquid formulationcontaining an antibody in a glutamate buffer and/or a citrate buffer.US2009/0280129 (Genentech describes high concentration antibody andprotein formulations.

There is therefore a great need for a stable high-concentratedpharmaceutical antibody composition having a low and feasible viscositywhich is suitable for subcutaneous administration, such as in a ready touse device. Furthermore, from a patient point of view it would be highlydesirable to have room temperature stable products. At this moment,there are no marketed mAb formulations where storage at room temperatureis a possibility throughout the shelf life of the drug product.Typically, increased protein degradation occurs forming an un-acceptablyhigh level of aggregates and protein related impurities, which may giverise to immunogenic reactions.

Many of the marketed mAb products contain surfactants in theirformulation. Typically, surfactants are added in order to reduceinterfacial stress which can induce protein aggregation and particleformation leading to unacceptable product quality. Examples ofinterfacial stress could be contact of the protein with i) air ii)container closure material, such as rubber plunger, piston, glass,pre-filled syringes iii) production related materials, such as steeltanks, tubings and pumps iv) ice, during freeze/thaw, etc. However,surfactants such as polysorbates typically contain a residue ofperoxides which may oxidize the protein molecule leading to acompromised product quality. Furthermore, from a manufacturing point ofview addition of polysorbates requires an extra step in the productionsince ultra/diafiltration is challenging to conduct when the formulationcontains the said polysorbates. The formation of oxidized products is achallenging issue, therefore a careful handling of polysorbates isrequired in order to control the formation of oxidized products. Thus,it would be desirable to design formulations without surfactants, bothfrom a stability- and manufacturing point of view.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, the invention provides astable, liquid composition comprising a protein, a salt and/or a buffer,characterised in that the total concentration of said salt and/or bufferis lower than 100 mM.

According to another aspect of the invention, there is provided astable, liquid composition comprising protein, a salt and/or a buffer,wherein the total concentration of the salt and/or buffer is lower than60 mM.

According to another aspect of the invention, there is provided astable, liquid protein composition, that is stable at room temperature.

According to another aspect of the invention, there is provided astable, liquid composition, wherein the concentration of the protein isbetween 100 mg/ml and 300 mg/ml.

According to another aspect of the invention, there is provided astable, liquid protein composition where the amino acid, L-arginine isused as a stabilizer.

According to another aspect of the invention, there is provided a stableprotein composition as defined herein for use in therapy.

According to another aspect of the invention, the invention provides aprotein composition without adding surfactant which is both stable andfeasible to produce.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect of the invention, the invention provides astable, liquid composition comprising a protein, a salt and/or a buffer,characterised in that the total concentration of said salt and buffer islower than 100 mM.

Surprisingly, it has been found that stable compositions of protein withlow amounts of salt and buffer has a low and feasible viscosity, such asa viscosity of <50 cP at 25° C. Low viscosity of pharmaceuticalformulations is especially desirable for subcutaneous injection, but isalso desirable for other liquid formulations, where it for instanceimproves the handling of the formulation.

The term “stable composition” refers to a composition with satisfactoryphysical stability, satisfactory chemical stability or satisfactoryphysical and chemical stability.

The term “physical stability” of the protein composition as used hereinrefers to the tendency of the protein to form biologically inactiveand/or insoluble aggregates of the protein as a result of exposure ofthe protein to thermo-mechanical stresses and/or interaction withinterfaces and surfaces that are destabilizing, such as hydrophobicsurfaces and interfaces. Physical stability of the aqueous proteincompositions is evaluated by means of visual inspection and/or turbiditymeasurements after exposing the composition filled in suitablecontainers (e.g. cartridges or vials). It is an inherent quality ofhighly concentrated formulations of mabs to exhibit opalescence due toRaleigh scattering. Thus, a composition cannot be classified asphysically unstable with respect to protein aggregation, when it showsvisual turbidity in daylight. However, when there are precipitates orphase separation visible in day light the formulation is classified asphysically unstable.

The term “chemical stability” of the protein composition as used hereinrefers to chemical covalent changes in the protein structure leading toformation of chemical degradation products with potential lessbiological potency and/or potential increased immunogenic propertiescompared to the native protein structure. Various chemical degradationproducts can be formed depending on the type and nature of the nativeprotein and the environment to which the protein is exposed. Eliminationof chemical degradation can most probably not be completely avoided andincreasing amounts of chemical degradation products is often seen duringstorage and use of the protein composition is well-known by the personskilled in the art. Most proteins are prone to deamidation, a process inwhich the side chain amide group in glutaminyl or asparaginyl residuesis hydrolysed to form a free carboxylic acid. Other degradation pathwaysinvolve formation of high molecular weight transformation products wheretwo or more protein molecules are covalently bound to each other throughtransamidation and/or disulfide interactions leading to formation ofcovalently bound dimer, oligomer and polymer degradation products(Stability of Protein Pharmaceuticals, Ahern. T. J. & Manning M. C.,Plenum Press, New York 1992). Oxidation (of for instance methionineresidues) can be mentioned as another variant of chemical degradation.The chemical stability of the protein composition can be evaluated bymeasuring the amount of the chemical degradation products at varioustime-points after exposure to different environmental conditions (theformation of degradation products can often be accelerated by forinstance increasing temperature). The amount of each individualdegradation product is often determined by separation of the degradationproducts depending on molecule size and/or charge using variouschromatography techniques (e.g. SEC-HPLC and/or RP-HPLC).

SEC-HPLC is in particular used for quantification of protein aggregates.The samples may for instance be analysed using a TSK G3000 SWXL column,isocratic elution and subsequent UV detection at 214 nm. This method isused to determine monomeric IgG content and % HMWP consisting of dimericspecies or larger which are separated according to size by the gelresin. The monomeric content and % HMWP are determined relative to thetotal protein content detected by the method.

Hence, as outlined above, a stable composition refers to a compositionwith satisfactory physical stability, satisfactory chemical stability orsatisfactory physical and chemical stability. A satisfactory stabilityof a formulation may be one wherein less than 10% and preferably lessthan 5% of the protein is as an aggregate (HMWP) in the formulation. Ingeneral, a composition must be stable during use and storage (incompliance with recommended use and storage conditions) until theexpiration date is reached.

Viscosity as used herein is used as the absolute viscosity also termeddynamic viscosity. Measurements are done by the cone and plate techniquewith a Peltier element set at 25° C., and where a well defined shearstress gradient is applied to a sample and the resulting shear rate ismeasured. The viscosity is the ratio of the shear stress to the shearrate. Absolute viscosity is expressed in units of centipoise (cP) at 25°C.

The term “room temperature” as used herein, means a temperature of theroom and where some kind of a cooling effect is not required. A roomtemperature is between 15 and 30° C., such as between 20 and 30° C.,such as 20° C., 25° C. or 30° C.

The term “protein”, “polypeptide” and “peptide” as used herein means acompound composed of at least five constituent amino acids connected bypeptide bonds. The constituent amino acids may be from the group of theamino acids encoded by the genetic code and they may be natural aminoacids which are not encoded by the genetic code, as well as syntheticamino acids. Natural amino acids which are not encoded by the geneticcode are e.g. hydroxyproline, y-carboxyglutamate, ornithine,phosphoserine, D-alanine and D-glutamine. Synthetic amino acids compriseamino acids manufactured by chemical synthesis, i.e. D-isomers of theamino acids encoded by the genetic code such as D-alanine and D-leucine,Aib (a-aminoisobutyric acid), Abu (α-aminobutyric acid), Tle(tert-butylglycine), β-alanine, 3-aminomethyl benzoic acid andanthranilic acid.

In one embodiment, the total concentration of salt and buffer is 95 mMor lower, such as any one of 90, 85, 80, 75, 70, 65 or 60 mM or lower.In one embodiment, the total concentration of salt and buffer is lowerthan 60 mM, such as 50 mM or lower, such as 45, 40, 35, 33, 30, 25, 20mM or lower.

In some embodiments, the salt can have a buffering capacity at therelevant pH, and in some embodiments, the buffer may be a salt. Thecritical feature is that the total concentration of salt and buffer doesnot exceed the stated values.

In one embodiment, the salt is an inorganic salt, or an organic salt ora combination of one or more of these. In one embodiment, the salt isselected from the group consisting of sodium chloride, magnesiumchloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulphate,ammonium chloride, calcium chloride, arginine hydrochloride, zincchloride, sodium acetate, amino acids or a combination thereof.

In one embodiment, the salt is sodium chloride or magnesium chloride,optionally in combination with other salts. In one embodiment, the saltis arginine hydrochloride. In one embodiment, the salt is a combinationof an inorganic salt and arginine hydrochloride.

In one embodiment, the salt is an amino acid. In one embodiment theL-stereoisomer of the amino acid is used. In one embodiment, the saltselected from arginine, glycine, lysine, aspartic acid, or glutamicacid, or a combination thereof. In one embodiment, the amino acid isarginine or glycine. In a further embodiment, the amino acid isarginine, such as L-arginine. The amino acid can be added to thecomposition in its salt form or in its free form, whatever is suitable.

In one embodiment, the salt (or combination of salts) is present in aconcentration of between 0 and 100 mM. In one embodiment, the totalconcentration of salt is 100 mM or lower, such as 50 mM, 40 mM, 35 mM,33 mM, 30 mM, 25 mM or lower.

It has surprisingly been found that the amino acid, L-arginine, acts asa stabilizer, and that the presence of L-arginine has a statisticallysignificant stabilising effect against the formation of HMWP aggregatesin high concentration liquid formulations of proteins, such asantibodies. Thus, the invention also provides a stable liquidcomposition comprising an antibody and arginine at a concentration ofbetween 5 mM and 100 mM, such as or lower, such as 50 mM, 40 mM, 35 mM,33 mM, 30 mM, 25 mM or lower. In one embodiment, the buffer is asuitable pharmaceutically acceptable buffer, which comprises both apharmaceutically acceptable base and a pharmaceutically acceptable acid.In one embodiment, the buffer has a pKa of between 4 and 8.

Examples of pharmaceutically acceptable acid and bases may includeinorganic as well as organic non-toxic acid/ bases such as it iswell-known in the art. Examples are disodium acetate, sodium carbonate,citrate, glycylglycine, histidine, glycine, lysine, arginine, maleate,succinate, sodium dihydrogen phosphate, disodium hydrogen phosphate,sodium phosphate, and tris(hydroxymethyl)-amino methane, or mixturesthereof. Each one of these specific buffers constitutes an alternativeembodiment of the invention. In one embodiment, the pharmaceuticallyacceptable buffer comprises histidine, maleate, succinate, phosphate, ortris(hydroxymethyl)-amino methane.

In one embodiment, the buffer has a pKa value ±1 pH unit from the targetpH of the composition.

In one embodiment, the composition is buffered to a pH of between 5 and7, such as a pH of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9,6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0 or to a pH asdefined by any ranges there between. In one embodiment, the compositionis buffered to a pH of 5.0, 5.5, 6.0, 6.5 or 7.0. In one embodiment, thecomposition is buffered to a pH of between 6.0 and 6.5. In oneembodiment, the composition is buffered to a pH of 6.0 or 6.5.

In one embodiment, the composition additionally comprises a surfactant.In one embodiment of the invention the surfactant is selected from adetergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylatedmonoglycerides, sorbitan fatty acid esters,polyoxypropylene-polyoxyethylene block polymers (eg. poloxamers such asPluronic® F68, poloxamer 188 and 407, Triton X-100), polyoxyethylenesorbitan fatty acid esters, polyoxyethylene and polyethylene derivativessuch as alkylated and alkoxylated derivatives (polysorbates, e.g.polysorbat 20, polysorbat 40, polysorbat 80 and Brij-35), monoglyceridesor ethoxylated derivatives thereof, diglycerides or polyoxyethylenederivatives thereof, alcohols, glycerol, lectins and phospholipids (eg.phosphatidyl serine, phosphatidyl choline, phosphatidyl ethanolamine,phosphatidyl inositol, diphosphatidyl glycerol and sphingomyelin),derivates of phospholipids (eg. dipalmitoyl phosphatidic acid) andlysophospholipids (eg. palmitoyl lysophosphatidyl-L-serine and1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine orthreonine) and alkyl, alkoxyl(alkyl ester), alkoxy(alkylether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g.lauroyl and myristoyl derivatives of lysophosphatidylcholine,dipalmitoylphosphatidylcholine, and modifications of the polar headgroup, that is cholines, ethanolamines, phosphatidic acid, serines,threonines, glycerol, inositol, and the positively charged DODAC, DOTMA,DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, andglycerophospholipids (eg. cephalins), glyceroglycolipids (eg.galactopyransoide), sphingoglycolipids (eg. ceramides, gangliosides),dodecylphosphocholine, hen egg lysolecithin, fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids andsalts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitinesand derivatives, N^(α)-acylated derivatives of lysine, arginine orhistidine, or side-chain acylated derivatives of lysine or arginine,N^(α)-acylated derivatives of dipeptides comprising any combination oflysine, arginine or histidine and a neutral or acidic amino acid,N^(α)-acylated derivative of a tripeptide comprising any combination ofa neutral amino acid and two charged amino acids, DSS (docusate sodium,CAS registry no [577-11-7]), docusate calcium, CAS registry no[128-49-4]), docusate potassium, CAS registry no [7491-09-0]), SDS(sodium dodecyl sulphate or sodium lauryl sulphate), sodium caprylate,cholic acid or derivatives thereof, bile acids and salts thereof andglycine or taurine conjugates, ursodeoxycholic acid, sodium cholate,sodium deoxycholate, sodium taurocholate, sodium glycocholate,N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic(alkyl-aryl-sulphonates) monovalent surfactants, zwitterionicsurfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates,3-cholamido-1-propyldimethylammonio-1-propanesulfonate, cationicsurfactants (quaternary ammonium bases) (e.g. cetyl-trimethylammoniumbromide, cetylpyridinium chloride), non-ionic surfactants (eg. Dodecylβ-D-glucopyranoside), poloxamines (eg. Tetronic's), which aretetrafunctional block copolymers derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine, or the surfactantmay be selected from the group of imidazoline derivatives, or mixturesthereof. Each one of these specific surfactants constitutes analternative embodiment of the invention. In one embodiment, thesurfactant is polysorbate 80 (i.e. Tween™80).

The use of a surfactant in pharmaceutical compositions is well-known tothe skilled person. For convenience reference is made to Remington: TheScience and Practice of Pharmacy, 20^(th) edition, 2000.

In one embodiment, the surfactant is present within the composition inan amount of below 0.01%. In one embodiment, the surfactant is presentwithin the composition in an amount of below 0.0075%, i.e between 0.001%and 0.005%, such as 0.001%.

In one embodiment, no surfactant is present. Surprisingly, it has beenfound that compositions of protein can be stable with both low amountsof salt, low amount of buffer or low amount of salt and buffer andwithout any addition of surfactant.

In one embodiment, the composition additionally comprises a tonicitymodifying agent. Examples of suitable tonicity modifying agents includesalts (e.g sodium chloride), polyhydric alcohols (e.g propyleneglycol,glycerol, xyllitol, mannitol or D-sorbitol), monosaccarides (glucose ormaltose), di saccarides (e.g sucrose), amino acids (L-glycine,L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophane,threonine), polyethylen glycols (e.g PEG 400) or mixtures thereof. Inone embodiment, the tonicity modifying agent is sucrose, mannitol orpropylene glycol. In a further embodiment, the tonicity modifying agentis sucrose. In some embodiments, the buffer and/or salt of thecomposition (as described above) also acts as tonicity modifier or thetonicity modifier will act as a buffer and/or salt (and theconcentration of the tonicity modifier will therefore in such cases becalculated as such).

In one embodiment, the tonicity modifying agent is present within thecomposition in an amount of between 50 and 250 mM, such as between 100and 200 mM, for example any one of 100, 110, 120, 130, 140, 150, 160,170, 180, 190 or 200 or any ranges there between. In one embodiment, thetonicity modifying agent is present within the composition in an amountof 150 mM.

In one embodiment, the composition is isotonic.

In one embodiment, the protein is an immunoglobulin. In one embodiment,the protein is an antibody. In one embodiment, the protein is amonoclonal antibody (mAb). In one embodiment, the protein is an IgG4antibody.

The term “antibody” covers monoclonal antibodies (including full lengthantibodies which have an immunoglobulin Fc region), antibodycompositions with polyepitopic specificity, bispecific antibodies,diabodies, and single-chain molecules, as well as antibody fragments(e.g., Fab, F(ab)₂, and Fv).

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. Monoclonal antibodies are highly specific, being directedagainst a single antigenic site. Furthermore, in contrast toconventional (polyclonal) antibody preparations which typically includedifferent antibodies directed against different determinants (epitopes),each monoclonal antibody is directed against a single determinant on theantigen. In addition to their specificity, the monoclonal antibodies areadvantageous in that they are synthesized by the hybridoma culture,uncontaminated by other immunoglobulins. The modifier “monoclonal”indicates the character of the antibody as being obtained from asubstantially homogeneous population of antibodies, and is not to beconstrued as requiring production of the antibody by any particularmethod. For example, the monoclonal antibodies to be used in accordancewith the present invention may be made by the hybridoma method firstdescribed by Kohler et al., Nature, 256: 495 (1975), or may be made byrecombinant DNA methods (see, e. g., U. S. Pat. No. 4,816,567). The“monoclonal antibodies” may also be isolated from phage antibodylibraries using the techniques described in Clackson et al., Nature,352: 624-628 (1991) and Marks et al., J. Mol. Biol., 222: 581-597(1991), for example.

The monoclonal antibodies herein may extend to include “chimeric”antibodies (immunoglobulins) in which a portion of the heavy and/orlight chain is identical with or homologous to corresponding sequencesin antibodies derived from a particular species or belonging to aparticular antibody class or subclass, while the remainder of the chain(s) is (are) identical with or homologous to corresponding sequences inantibodies derived from another species or belonging to another antibodyclass or subclass, as well as fragments of such antibodies, so long asthey exhibit the desired biological activity (U.S. Pat. No. 4,816,567;Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)).

Examples of suitable antibodies, which may be formulated in a stablecomposition of the invention include: 3F8, Abagovomab, Abciximab, ACZ885(canakinumab), Adalimumab, Adecatumumab, Afelimomab, Afutuzumab,Alacizumab pegol, Alemtuzumab, Altumomab pentetate, Anatumomabmafenatox, Anrukinzumab (IMA-638), Apolizumab, Arcitumomab, Aselizumab,Atlizumab (tocilizumab), Atorolimumab, Bapineuzumab, Basiliximab,Bavituximab, Bectumomab, Belimumab, Bertilimumab, Besilesomab,Bevacizumab, Biciromab, Bivatuzumab mertansine, Blinatumomab,Brentuximab vedotin, Briakinumab, Canakinumab, Cantuzumab mertansine,Capromab pendetide, Catumaxomab, Cedelizumab, Certolizumab pegol,Cetuximab, Citatuzumab bogatox, Cixutumumab, Clenoliximab, Clivatuzumabtetraxetan, ONTO 148 (golimumab), ONTO 1275 (ustekinumab), Conatumumab,Dacetuzumab, Daclizumab, Denosumab, Detumomab, Dorlimomab aritox,Dorlixizumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab,Efalizumab, Efungumab, Elsilimomab, Enlimomab pegol, Epitumomabcituxetan, Epratuzumab, Erlizumab, Ertumaxomab, Etaracizumab,Exbivirumab, Fanolesomab, Faralimomab, Felvizumab, Fezakinumab,Figitumumab, Fontolizumab, Foravirumab, Fresolimumab, Galiximab,Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, Golimumab,Gomiliximab, Ibalizumab, Ibritumomab tiuxetan, Igovomab, Imciromab,Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab,Iratumumab, Keliximab, Labetuzumab, Lebrikizumab, Lemalesomab,Lerdelimumab, Lexatumumab, Libivirumab, Lintuzumab, Lucatumumab,Lumiliximab, Mapatumumab, Maslimomab, Matuzumab, Mepolizumab,Metelimumab, Milatuzumab, Minretumomab, Mitumomab, Morolimumab,Motavizumab, Muromonab-CD3, MYO-029 (stamulumab), Nacolomab tafenatox,Naptumomab estafenatox, Natalizumab, Nebacumab, Necitumumab,Nerelimomab, Nimotuzumab, Nofetumomab merpentan, Ocrelizumab,Odulimomab, Ofatumumab, Omalizumab, Oportuzumab monatox, Oregovomab,Otelixizumab, Pagibaximab, Palivizumab, Panitumumab, Panobacumab,Pascolizumab, Pemtumomab, Pertuzumab, Pexelizumab, Pintumomab,Priliximab, Pritumumab, PRO 140, Rafivirumab, Ramucirumab, Ranibizumab,Raxibacumab, Regavirumab, Reslizumab, Rilotumumab, Rituximab,Robatumumab, Rontalizumab, Rovelizumab, Ruplizumab, Satumomab,Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Siplizumab,Solanezumab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab,Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomabpaptox, Tefibazumab, Telimomab aritox, Tenatumomab, Teneliximab,Teplizumab, TGN1412, Ticilimumab (tremelimumab), Tigatuzumab, TNX-355(ibalizumab), TNX-650, TNX-901 (talizumab), Tocilizumab (atlizumab),Toralizumab, Tositumomab, Trastuzumab, Tremelimumab, Tucotuzumabcelmoleukin, Tuvirumab, Urtoxazumab, Ustekinumab, Vapaliximab,Vedolizumab, Veltuzumab, Vepalimomab, Visilizumab, Volociximab,Votumumab, Zalutumumab, Zanolimumab, Ziralimumab, Zolimomab aritox andthe like.

In one embodiment, the antibody is a monoclonal anti-IL20 antibody. Inone embodiment, the antibody is an anti-IL20 antibody as described inWO2010/000721. In one embodiment, the anti-IL20 monoclonal antibody is15D2 or 5B7 as described in WO2010/000721.

In one embodiment, the antibody is a monoclonal anti-TFPI monoclonalantibody. In one embodiment, the antibody is an anti-TFPI antibody asdescribed in PCT2009EP067598. In one embodiment, the anti-TFPImonoclonal antibody is HzTFPI4F36 as described in PCT2009EP067598.

In one embodiment, the antibody is a monoclonal anti-C5aR monoclonalantibody. In one embodiment, the antibody is an anti-C5aR antibody asdescribed in WO2009/103113. In one embodiment, the anti-C5aR monoclonalantibody is 7F3 as described in WO2009/103113.

In one embodiment, the antibody is a monoclonal anti-NKG2D monoclonalantibody. In one embodiment, the antibody is an anti-NKG2D antibody asdescribed in WO2009/077483. In one embodiment, the anti-NKG2D monoclonalantibody is MS as described in WO2009/077483.

In one embodiment, the antibody is a monoclonal anti-NKG2A monoclonalantibody. In one embodiment, the antibody is an anti-NKG2A antibody asdescribed in WO2008/009545. In one embodiment, the anti-NKG2A monoclonalantibody is humZ270 as described in WO2008/009545.

It will be appreciated that the invention finds particular utility wherethe protein is present within the composition in high concentrations.Thus, in one embodiment, the protein is present in a concentration of 50mg/ml or more, such as 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150,200, 250, 300 mg/ml or more. In one embodiment, the protein is presentwithin the composition in an amount of between 50 mg/ml and 300 mg/ml,for instance between 50 mg/ml and 250 mg/ml, such as between 50 mg/mland 200 mg/ml, for instance between 50 mg/ml and 150 mg/ml. In oneembodiment, the protein is present in a concentration of between 75mg/ml and 300 mg/ml, for instance between 75 mg/ml and 250 mg/ml, suchas between 75 mg/ml and 200 mg/ml, for instance between 75 mg/ml and 150mg/ml. In one embodiment, the protein is present in a concentration ofbetween 100 mg/ml and 300 mg/ml, for instance between 100 mg/ml and 250mg/ml, such as between 100 mg/ml and 200 mg/ml, for instance between 100mg/ml and 150 mg/ml.

In one embodiment, the stable compositions of the invention have aviscosity of 50 cP or less when measured at 25° C., such as any of lessthan 45, 40, 35, 30, 25, 20, 15, 10, 5 or 1 cP. In particular, thestable compositions of the invention have a viscosity of 5 cP or lesswhen measured at 25° C.

Employing a high concentrated formulation containing for instance 100mg/ml protein and lower than 100 mM of the sum of salt and bufferconcentration renders a relatively low-viscous formulation (5 cP at 25°C. for an anti-IL20 antibody) which is stable at storage temperature of2-8° C. In one embodiment, the formulation is also stable at highertemperatures such as room temperature. The formulation is suitable foruse in ready-to-use devices with a small needle size conferring enhancedpatient convenience as compared to a marketed ready to use product (forinstance Humira® which employs a 27G needle and 50 mg/ml of antibodyconcentration).

In one embodiment, a protein composition of the invention comprises:

-   -   (a) ≧50 mg/ml antibody;    -   (b) 30 mM or lower of a in-organic salt, such as sodium chloride        or magnesium chloride;    -   (c) 0-25 mM of an amino acid, such as arginine or glycine;    -   (d) 50 mM or lower of a buffer such as histidine buffer;    -   (e) 0.001-0.005% of a non-ionic surfactant;    -   (f) 100-200 mM of a tonicity modifying agent, such as sucrose,        propylene glycol, glycerol, mannitol or D-sorbitol;        buffered to a pH of between 5 and 7.

In one embodiment, a protein composition of the invention comprises:

-   -   (a) 100 mg/ml antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM sucrose;        buffered to a pH of between 5 and 7.

In one embodiment, the stable protein composition comprises:

-   -   (a) 100 mg/ml antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM mannitol;        buffered to a pH of between 5 and 7.

In one embodiment, the stable protein composition comprises:

-   -   (a) 100 mg/ml antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM sucrose;        buffered to a pH of 6.0 to 6.5.

In one embodiment, the stable protein composition comprises:

-   -   (a) 100 mg/ml antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 150 mM sucrose;        buffered to a pH between 5 and 7.

Compositions of the invention have surprisingly demonstrated stabilitytowards formation of HMWP at room temperature (here measured at 25° C.)for 12 months and at 5° C. for up to 24 months where there is nodetectable increase of % HMWP. In addition, several compositions of theinvention typically show that only 2-7% of HMWP is formed over 3 monthsat 40° C. suggesting an interesting thermostable formulation despitehaving a low total concentration of salt and buffer.

It will be apparent to those skilled in the art of pharmaceuticalcompositions that the stable protein compositions hereinbefore describedmay be prepared in accordance with standard procedures (Luo R et al.High-concentration UF/DF of a monoclonal antibody. Strategy foroptimization and scale-up, Bioprocess Int. 4, 44-48 (2006)). Forexample, the stable protein compositions may typically be prepared byfirst dia-filtrating the protein at a concentration of 50 mg/ml or moreby use of Tangential Flow Filtration (TFF). Subsequently, the formulatedproduct, except for the addition of a surfactant (where applicable) isultra-filtrated to 100 mg/ml or higher concentrations after whichsurfactant may be added.

It is possible that other ingredients may be present in thepharmaceutical composition of the present invention. Such additionalingredients may include cosolvents, wetting agents, emulsifiers,antioxidants, bulking agents, chelating agents, metal ions, oleaginousvehicles, proteins (e.g., human serum albumin, gelatine or proteins) anda zwitterion. Such additional ingredients, of course, should notadversely affect the overall stability of the pharmaceutical formulationof the present invention.

In one embodiment, the pharmaceutical compositions of the invention arestable for more than 6 weeks of usage and for more than 3 years ofstorage.

In one embodiment, the pharmaceutical compositions of the invention arestable for more than 4 weeks of usage and for more than 3 years ofstorage.

In one embodiment, the pharmaceutical compositions of the invention arestable for more than 4 weeks of usage and for more than two years ofstorage.

In one embodiment, the pharmaceutical compositions of the invention arestable for more than 2 weeks of usage and for more than two years ofstorage.

In one embodiment, the pharmaceutical compositions of the invention arestable for more than 1 week of usage and for more than six months ofstorage.

According to a second aspect of the invention, there is provided astable protein composition as defined herein for use in therapy.

The term “treatment” and “treating” as used herein means the managementand care of a patient for the purpose of combating a condition, such asa disease or a disorder. The term is intended to include the fullspectrum of treatments for a given condition from which the patient issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relieve the symptoms andcomplications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. The patient to be treated is preferably amammal; in particular a human being, but it may also include animals,such as dogs, cats, cows, sheep and pigs.

For example, the compositions of anti-IL20 antibodies of the presentinvention may be used in the treatment of an inflammatory disease, inparticular autoinflammatory diseases, such as psoriasis, systemic lupuserythomatosus, rheumatoid arthritis, Crohn's disease and psoriaticarthritis or otherwise as described in WO2010/000721.

Thus according to a further aspect, the invention provides a method oftreating such an inflammatory disease which comprises administering to apatient a therapeutically effective amount of a composition of ananti-IL20 antibody of the present invention.

The invention also provides a composition of an anti-IL20 antibody ofthe present invention for use in the treatment of such an inflammatorydisease.

The invention also provides the use of a composition of an anti-IL20antibody of the present invention in the manufacture of a medicament forthe treatment of such an inflammatory disease.

The invention also provides a pharmaceutical composition comprising acomposition of an anti-IL20 antibody of the present invention for use inthe treatment of such an inflammatory disease.

For example, the compositions of anti-TFPI antibodies of the presentinvention may be used in the treatment of a coagulopathy (bleedingdisorder), such as haemophilia A, with or without inhibitors, andhaemophilia B, with or without inhibitors or otherwise as described inPCT2009EP067598.

Thus according to a further aspect, the invention provides a method oftreating a coagulopathy which comprises administering to a patient atherapeutically effective amount of a composition of an anti-TFPIantibody of the present invention.

The invention also provides a composition of an anti-TFPI antibody ofthe present invention for use in the treatment of a coagulopathy.

The invention also provides the use of a composition of an anti-TFPIantibody of the present invention in the manufacture of a medicament forthe treatment of a coagulopathy.

The invention also provides a pharmaceutical composition comprising acomposition of an anti-IL20 antibody of the present invention for use inthe treatment of a coagulopathy.

For example, the compositions of anti-C5aR antibodies of the presentinvention may be used in the treatment of an inflammatory disease, inparticular autoinflammatory diseases, such as psoriasis, systemic lupuserythomatosus, rheumatoid arthritis, Crohn's disease and psoriaticarthritis or otherwise as described in WO2009/103113.

Thus according to a further aspect, the invention provides a method oftreating an inflammatory disease which comprises administering to apatient a therapeutically effective amount of a composition of ananti-C5aR antibody of the present invention.

The invention also provides a composition of an anti-C5aR antibody ofthe present invention for use in the treatment of an inflammatorydisease.

The invention also provides the use of a composition of an anti-C5aRantibody of the present invention in the manufacture of a medicament forthe treatment of an inflammatory disease.

The invention also provides a pharmaceutical composition comprising acomposition of an anti-C5aR antibody of the present invention for use inthe treatment of an inflammatory disease.

For example, the compositions of anti-NKG2D antibodies of the presentinvention may be used in the treatment of an inflammatory disease, inparticular autoinflammatory diseases, such as psoriasis, systemic lupuserythomatosus, rheumatoid arthritis, Crohn's disease and psoriaticarthritis or otherwise as described in WO2009/077483.

Thus according to a further aspect, the invention provides a method oftreating an inflammatory disease which comprises administering to apatient a therapeutically effective amount of a composition of ananti-NKG2D antibody of the present invention.

The invention also provides a composition of an anti-NKG2D antibody ofthe present invention for use in the treatment of an inflammatorydisease.

The invention also provides the use of a composition of an anti-NKG2Dantibody of the present invention in the manufacture of a medicament forthe treatment of an inflammatory disease.

The invention also provides a pharmaceutical composition comprising acomposition of an anti-NKG2D antibody of the present invention for usein the treatment of an inflammatory disease.

For example, the compositions of anti-NKG2A antibodies of the presentinvention may be used in the treatment of an inflammatory disease, inparticular autoinflammatory (also called autoimmune) diseases, such aspsoriasis, systemic lupus erythomatosus, rheumatoid arthritis, Crohn'sdisease and psoriatic arthritis or otherwise as described inWO2008/009545.

Thus according to a further aspect, the invention provides a method oftreating an inflammatory disease which comprises administering to apatient a therapeutically effective amount of a composition of ananti-NKG2A antibody of the present invention.

The invention also provides a composition of an anti-NKG2A antibody ofthe present invention for use in the treatment of an inflammatorydisease.

The invention also provides the use of a composition of an anti-NKG2Aantibody of the present invention in the manufacture of a medicament forthe treatment of an inflammatory disease.

The invention also provides a pharmaceutical composition comprising acomposition of an anti-NKG2A antibody of the present invention for usein the treatment of an inflammatory disease.

It is to be understood, that therapeutic and prophylactic (preventive)regimes represent separate aspects of the present invention.

The pharmaceutical formulations of the invention are generally suitablefor parenteral administration. Parenteral administration may beperformed by subcutaneous, intramuscular, intraperitoneal or intravenousinjection by means of a syringe, optionally a pen-like syringe.Alternatively, parenteral administration can be performed by means of aninfusion pump.

The invention is further described with reference to the followingnon-limiting examples.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1. shows a statistical analysis of the effect of main factors and2-factors interactions on the formation of % HMWP after the formulationshave been stored at 40° C. for 3 months.

FIG. 2. shows the statistical analysis of the effect of histidine andarginine on the formulation of % HMWP after formulations have beenstored at 40° C. for 3 months.

FIG. 3. shows the statistical analysis of the effect of histidine,sodium chloride (NaCl) and arginine on the viscosity of the formulation.

EXAMPLES Example 1

18 formulations were prepared (see below Table 1). The formulations wereprepared from a stock solution containing ca. 150 mg/ml of the mAb 1 and10 mM histidine buffer, pH 6.5. This stock solution was prepared byconventional UF/DF/UF. Stock solution of the excipients were preparedand mixed in the correct proportion using a Biomek® 2000, BeckmanCoulter robot system. The final formulations were filled in 3 mlPenfill® cartridges, type 1 glass. The piston in the cartridge wasadjusted to accommodate 0.6 ml which was also the filling volume. Theformulations were stored at 40° C. for three months and then analysedchemically, pharmaceutical chemically and biophysically. The increase inthe formation of protein aggregates (% HMWP) can be modelled using SASJMP 8.0 software. The data show that there is a positive effect on thestability of arginine which decreased the formation of proteinaggregates significantly. Similarly, the combined effect of histidineand NaCl also decreases the formation of protein aggregates. Sucrose andPolysorbate 80 (PS 80) weakly augments the formation of proteinaggregates.

TABLE 1 Composition of formulations PS 80 mAb 1 Histidine NaCl (mg/Sucrose Arginine % (mg/ml) (mM) (mM) ml) (mM) (mM) pH ΔHMWP 100 33 250.01 0 25 6.5 1.4 100 66 25 0.01 0 0 6.5 2.1 100 33 100 0.01 0 0 6.5 2.0100 66 100 0.01 0 25 6.5 1.7 100 33 25 0.05 0 0 6.5 2.3 100 66 25 0.05 025 6.5 1.8 100 33 100 0.05 0 25 6.5 1.8 100 66 100 0.05 0 0 6.5 1.8 10033 25 0.01 30 0 6.5 2.6 100 66 25 0.01 30 25 6.5 1.7 100 33 100 0.01 3025 6.5 1.6 100 66 100 0.01 30 0 6.5 1.6 100 33 25 0.05 30 25 6.5 1.5 10066 25 0.05 30 0 6.5 3.6 100 33 100 0.05 30 0 6.5 3.6 100 66 100 0.05 3025 6.5 1.9 100 49.5 62.5 0.03 15 12.5 6.5 1.8 100 49.5 62.5 0.03 15 12.56.5 1.8 PS = polysorbate

The statistical effect of main factors and 2-factors interactions on theformation of % HMWP, after the formulation has been stored at 40° C. forthree months is shown in FIG. 1.

Example 2

A mAb-solution is prepared by UF/DF/UF to a concentration >100 mg/mlincluding either 10 mM histidine or 10 mM NaCl. A solution containingthe excipients to be investigated is prepared and mixed with themAb-solution to the aimed concentration. pH is adjusted to the aimed pH.The formulations were filled in 3 ml Penfill® cartridges, type 1 glass.The piston in the cartridge was adjusted to accommodate 1.5 ml which wasalso the filling volume. The cartridges were stored at 5° C. and/or 25°C. and/or 40° C. Table 2 shows the various formulations prepared and theresulting viscosity and increase in aggregates (% HMWP).

Similar to Example 1 it is observed that arginine has an stabilisingeffect as it counteracts the formation of % HMWP. Histidine is alsoobserved to contain similar stabilising effect. Furthermore, it was alsoobserved that histidine, sodium chloride and arginine each have astatistically significant viscosity-lowering effect on theformulation—histidine having the most profound effect.

Interestingly, after 12 months at 25° C. the increase in % HMWP isvirtually non-existing which strongly indicates that there is apotential for a room temperature stable formulation (Table 2).

mAb1 is the 15D2 anti-IL20 antibody as described in WO2010/000721. mAb2is the anti-TFPI monoclonal antibody HzTFPI4F36 as described inPCT2009EP067598. mAb3 is the anti-C5aR monoclonal antibody hAb-Q asdescribed in WO2009/103113. mAb4 is the anti-NKG2D monoclonal antibodyMS as described in 2009/077483. mAb5 is the anti-NKG2A monoclonalantibody humZ270 as described in WO2008/009545

TABLE 2 Examples of formulations and their corresponding viscosity andchemical stability Conc of Storage Storage mAb temp time ΔHMWP ViscositymAb (mg/ml) Composition (° C.) (months) (%) (cP) mAb1 100 Histidine 33mM 5 12 0.0 5.4 NaCl 25 mM 5 24 0.0 PS 80 0.001% 25 3 0.2 Arginine 25 mM40 3 1.4 pH 6.5 mAb1 50 Histidine 33 mM 5 18 0.3 3.7 NaCl 25 mM 40 3 3.1PS 80 0.001% Arginine 25 mM pH 6.5 mAb1 100 Histidine 66 mM 5 12 0.1 5.9NaCl 25 mM 5 24 0.0 PS 80 0.001% 25 3 0.3 pH 6.5 40 3 2.1 mAb1 100Histidine 33 mM 5 12 0.3 5.5 NaCl 25 mM 5 24 0.0 PS 80 0.005% 25 3 0.5pH 6.5 40 3 2.3 mAb1 100 Histidine 33 mM 5 12 0.0 5.4 NaCl 25 mM 5 240.0 PS 80 0.001% 25 3 0.4 Sucrose 30 mM 40 3 2.6 pH 6.5 mAb1 50Histidine 33 mM 5 18 0.2 2.3 NaCl 25 mM 40 3 3.4 PS 80 0.005% Sucrose 30mM Arginine 25 mM pH 6.5 mAb1 100 Histidine 33 mM 5 12 0.0 5.9 NaCl 25mM 15 12 0.1 Arginine 25 mM 25 12 0.2 PS 80 0.001% 30 12 0.5 Sucrose 150mM 40 12 13.8 pH 6.5 mAb1 100 Histidine 10 mM 40 3 2.8 6.7 PS 80 0.001%Arginine 70 mM pH 6.5 mAb1 100 Histidine 10 mM 40 3 3.6 7.1 NaCl 70 mMPS 80 0.001% pH 6.5 mAb1 100 Histidine 10 mM 5 18 0.0 9.3 pH 6.5 40 36.1 mAb1 150 Histidine 33 mM 5 12 0.0 6.0 NaCl 25 mM 25 3 0.0 PS 800.001% 40 3 4.0 Arginine 25 mM pH 6.5 mAb1 100 Na-phosphate 10 mM 40 33.7 4.2 NaCl 25 mM PS 80 0.005% Arginine 25 mM pH 6.5 mAb1 100 Succinate10 mM 40 3 2.8 5.6 NaCl 25 mM PS 80 0.005% Arginine 25 mM pH 6.5 mAb1100 Na-citrate 10 mM 40 3 2.4 8.7 NaCl 25 mM PS 80 0.005% Arginine 25 mMpH 6.5 mAb1 100 Maleate 10 mM 40 3 2.9 4.8 NaCl 25 mM PS 80 0.005%Arginine 25 mM pH 6.51.7 mAb1 100 Tris (hydrxy- 40 3 2.5 3.9methyl-amino- methan) 10 mM NaCl 25 mM PS 80 0.005% Arginine 25 mM pH6.5 mAb2 150 Histidine 33 mM 40 1 1.1 10.0 NaCl 25 mM 40 3 3.7 PS 800.001% 5 12 0.1 Arginine 25 mM pH 6.0 mAb2 100 Histidine 33 mM 40 1 0.76.6 NaCl 25 mM 40 3 2.9 PS 80 0.001% 5 12 0.0 Arginine 25 mM pH 6.0 mAb2150 Histidine 10 mM 40 1 1.4 8.6 pH 6.0 40 3 4.5 5 12 0.1 mAb2 100Histidine 10 mM 40 1 0.9 9.5 pH 6.0 40 3 3.3 5 12 0.0 mAb3 100 Histidine50 mM 5 6 0.3 5.6 NaCl 25 mM 5 18 0.1 PS 80 0.005% 40 3 3.7 pH 6.5 mAb3100 Histidine 25 mM 5 6 0.8 6.5 NaCl 25 mM 5 18 1.3 PS 80 0.001% 40 35.3 pH 6.5 mAb3 100 Histidine 10 mM 5 6 0.6 7.1 NaCl 25 mM 5 18 1.3 pH6.5 40 2 2.8 mAb4 100 Histidine 33 mM 40 2 0.9 4.3 NaCl 25 mM 40 3 1.6PS 80 0.001% 5 12 0.3 Sucrose 150 mM Arginine 25 mM pH 6.0 mAb4 100Histidine 10 mM 40 2 3.4 4.3 pH 6.0 40 3 4.8 5 12 0.5 mAb5 100 Histidine33 mM 5 9 0.0 6.5 NaCl 25 mM 40 3 3.1 PS 80 0.001% Sucrose 150 mMArginine 25 mM pH 6.0 mAb5 100 Histidine 10 mM 5 9 0.2 7.3 pH 6.0 40 37.4 Conc. of mAb: the concentration of the stated antibody given inmg/ml. ΔHMWP (%): Determined by SE-HPLC. Viscosity: (cP) at 25° C. attime zero PS: polysorbate

The statistical effects of histidine og arginine on the formation of %HMWP after the formulation has been stored at 40° C. for 3 months, isshown in FIG. 2.

The statiscial effects of histidine, sodium chloride (NaCl) and arginineon the viscosity of the formulation is shown in FIG. 3.

Example 3

Formulations of mAbs have been prepared as mentioned in Example 2 withvariation only in the amount of surfactant. The robustness of theformulations have been assessed by storage stability at accelerated andstorage temperature (Table 3), and furthermore by mechanical agitationand freeze/thaw (Table 4). All formulations contain:

100 mg/ml mAb, 33 mM histidine, 25 mM arginine, 25 mM NaCl. 150 mMsucrose, 0-0.1 mg/ml Polysorbate 80. Formulation pH: 6.5 (mAb 1) and 6.0(mAb 4)

TABLE 3 Storage stability at accelerated and storage temperatureconditions. Formulations contain varying amounts of surfactant.Surfactant Storage ΔTurbidity concentration Storage time ΔHMWP* units*mAb (mg/ml) temp (° C.) (months) (%) at 340 nm Viscosity (cP) mAb 1 None5 9 0.0 0.02 6.0 40 3 1.6 0.26 mAb 1 0.01 5 9 0.0 0.00 6.5 40 3 1.6 0.19mAb 1 0.02 5 9 0.0 0.00 6.4 40 3 1.6 0.25 mAb 1 0.05 5 9 0.0 0.00 6.1 403 1.5 0.17 mAb 1 0.1  5 9 0.0 0.00 6.0 40 3 1.7 0.34 mAb 4 None 5 9 0.20.01 4.3 40 3 3.0 0.29 mAb 4 0.01 5 9 0.1 0.03 4.9 40 3 3.0 0.32 mAb 40.02 5 9 0.1 0.01 4.6 40 3 3.1 0.32 mAb 4 0.05 5 9 0.2 0.01 5.0 40 3 3.30.36 mAb 4 0.1  5 9 0.3 0.09 5.4 40 3 3.3 0.43 *The values arecalculated as: time point X minus time point zero. Viscosity measued at25° C. at time zero.

Visual appearance analysis has also been performed in light cabinet andarchitect lamp for all formulations to assess the possibility offormation of particles. At time zero all samples were found to be clearto slightly opalescent without any visible particles using bothanalytical methods. No difference has been observed during the storagestability period of the appearance of all formulations.

TABLE 4 Formulations of mAbs exposed to i) freeze-thaw stress (10 cyclesfrom −20° C. to ambient temperature) ii) mechanical agitation at ambienttemperature, and iii) combined rotation and thermal stress (37° C.)Freeze- Mechanical Rotation and thaw cycles agitation thermal stressSurfactant ΔTurbidity ΔTurbidity ΔTurbidity conc. units* units* units*mAb (mg/ml) at 340 nm at 340 nm at 340 nm mAb 1 None 0.05 0.00 0.11 mAb1 0.01 0.00 0.00 0.00 mAb 1 0.02 0.00 0.00 0.00 mAb 1 0.05 0.00 0.000.00 mAb 1 0.1  0.06 0.00 0.06 mAb 4 None 0.06 0.00 0.07 mAb 4 0.01 0.050.01 0.07 mAb 4 0.02 0.18 0.00 0.05 mAb 4 0.05 0.15 0.08 0.07 mAb 4 0.1 NA 0.15 0.14 *The values are calculated as: time point X minus timepoint zero. Viscosity measued at 25° C. at time zero.

Visual appearance analysis has also been performed in light cabinet andarchitect lamp for all formulations to assess the possibility offormation of particles. At time zero all samples were found to be clearto slightly opalescent without any visible particles using bothanalytical methods. No difference has been observed during the abovestress conditions. Furthermore, no increase in % HMWP could be detectedduring these stress conditions.

Example 4. Two batches (ca. 3 L) have been produced in pilot plantfacility according to regular fill finish conditions. The formulationwas filled in 3 ml Penfill® cartridges, type 1 glass. The piston in thecartridge was adjusted to accommodate 1 ml which was also the fillingvolume. The difference between the composition of the batches is thatone contains Polysorbate 80 whereas the other does not. The two drugproducts are exposed to accelerated temperature conditions andmechanical agitation (Table 5).

TABLE 5 Storage stability of two pilot production batches of mAb 1.ΔTur- Storage Storage bidity Vis- Composition temp time ΔHMWP* units*cosity (+/−PS 80) (° C.) (months) (%) at 340 nm (cP) Histidine 33 mM  53 0.3 0.00 3.5 NaCl 25 mM 25 3 0.6 0.00 Sucrose 150 mM 30 3 0.4 0.00Arginine 25 mM 40 3 2.1 0.46 pH 6.5 Ambient 0.5 0.3 0.00 temper- ature**Histidine 33 mM  5 3 0.3 0.00 3.4 NaCl 25 mM 25 3 0.6 0.00 Sucrose 150mM 30 3 0.4 0.00 Arginine 25 mM 40 3 2.5 N.A PS 80 0.001% Ambient 0.50.3 0.00 pH 6.5 temper- ature** *The values are calculated as: timepoint X minus time point zero. NA: not applicable. Viscosity measued at25° C. at time zero. **Mechanical agitation of drug product taking placeat ambient temperature for 2 weeks.

Example 5

A lab scale batch was prepared as in Example 2 and filled in 3.0 mlPenfill® cartridges, type 1 glass. The piston in the cartridge wasadjusted to accommodate 1.5 ml which was also the filling volume. Theeffect of air/water interfacial stress on the drug product was assessedby applying varying volume of air to the formulation, and exposing it tosevere temperature and mechanical stress conditions (Table 6)

TABLE 6 Influence on protein stability of volume of air added to drugproduct filled in 3.0 ml Penfill ® cartridges*. Protein stability wasassessed after rotational and thermal stress at 37° C. for 14 days.Volume of air added ΔTurbidity units** to drug product (μL) % ΔHMWP** at340 nm 0 0.0 0.11 25 0.0 0.12 50 0.0 0.12 100 0.1 0.13 *Drug productcontains: 100 mg/ml mAb 1, 33 mM histidine, 25 mM arginine, 25 mM NaCl,150 mM sucrose, 0.001% Polysorbate 80. **The values are calculated as:time point X minus time point zeroThe following is a non-limiting list of embodiments of the presentinvention.

Embodiment 1: A stable, liquid composition comprising a protein, a saltand/or a buffer, characterised in that the total concentration of saidsalt and buffer is lower than 100 mM.

Embodiment 2: A composition according to embodiment 1, wherein the totalconcentration of said salt and buffer is between 5 and 100 mM.

Embodiment 3: A composition according to embodiment 1 or 2, wherein thetotal concentration of salt and buffer is between 5 and 95 mM.

Embodiment 4: A composition according to any of embodiments 1 to 3,wherein the total concentration of salt and buffer is between 5 and 90mM.

Embodiment 5: A composition according to any of embodiments 1 to 4,wherein the total concentration of salt and buffer is between 5 and 85mM.

Embodiment 6: A composition according to any of embodiments 1 to 5,wherein the total concentration of salt and buffer is between 5 and 80mM.

Embodiment 7: A composition according to any of embodiments 1 to 6,wherein the total concentration of salt and buffer is between 5 and 75mM.

Embodiment 8: A composition according to any of embodiments 1 to 7,wherein the total concentration of salt and buffer is between 5 and 70mM.

Embodiment 9: A composition according to any of embodiments 1 to 8,wherein the total concentration of salt and buffer is between 5 and 65mM.

Embodiment 10: A composition according to any of embodiments 1 to 9,wherein the total concentration of salt and buffer is between 5 and 60mM.

Embodiment 11: A composition according to any of embodiments 1 to 10,wherein the total concentration of salt and buffer is between 5 and 55mM.

Embodiment 12: A composition according to any of embodiments 1 to 11,wherein the total concentration of salt and buffer is between 5 and 50mM.

Embodiment 13: A composition according to any of embodiments 1 to 12,wherein the total concentration of salt and buffer is between 5 and 45mM.

Embodiment 14: A composition according to any of embodiments 1 to 13,wherein the total concentration of salt and buffer is between 5 and 40mM.

Embodiment 15: A composition according to any of embodiments 1 to 14,wherein the total concentration of salt and buffer is between 5 and 35mM.

Embodiment 16: A composition according to any of embodiments 1 to 15,wherein the total concentration of salt and buffer is between 5 and 30mM.

Embodiment 17: A composition according to any of embodiments 1 to 16,wherein the total concentration of salt and buffer is between 5 and 25mM.

Embodiment 18: A composition according to embodiment 1 or 2, wherein theconcentration of the buffer is 100 or lower.

Embodiment 19: A composition according to any of embodiments 1 to 12,wherein the concentration of the buffer is 50 or lower.

Embodiment 20: A composition according to any of embodiments 1 to 13,wherein the concentration of the buffer is 45 or lower.

Embodiment 21: A composition according to any of embodiments 1 to 14,wherein the concentration of the buffer is 40 or lower.

Embodiment 22: A composition according to any of embodiments 1 to 15,wherein the concentration of the buffer is 35 or lower.

Embodiment 23: A composition according to embodiment 22, wherein theconcentration of the buffer is 33 mM or lower.

Embodiment 24: A composition according to embodiment 1 or 2, wherein theconcentration of the salt is 100 or lower.

Embodiment 25: A composition according to any of embodiments 1 to 12,wherein the concentration of the salt is 50 or lower.

Embodiment 26: A composition according to any of embodiments 1 to 13,wherein the concentration of the salt is 45 or lower.

Embodiment 27: A composition according to any of embodiments 1 to 14,wherein the concentration of the salt is 40 or lower.

Embodiment 28: A composition according to any of embodiments 1 to 15,wherein the concentration of the salt is 35 or lower.

Embodiment 29: A composition according to any of embodiments 1 to 16,wherein the concentration of the salt is 25 mM or lower.

Embodiment 30: A composition according to any embodiments 1 to 29,wherein a buffer is present, and the buffer has a pKa between 4 to 8.

Embodiment 31: A composition according to embodiment 30, wherein thebuffer has a pKa between 5 to 7.

Embodiment 32: A composition according to any of embodiments 1 to 30,wherein a buffer is present, and the buffer is dosodium acetate, sodiumcarbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine,maleate, succinate, sodium dihydrogen phosphate, disodium hydrogenphosphate, sodium phosphate, or tris(hydroxymethyl)-amino methane, ormixtures thereof.

Embodiment 33: A composition according to embodiment 32, wherein thebuffer is histidine, maleate, succinate, phosphate, ortris(hydroxymethyl)-amino methane.

Embodiment 34: A composition according to embodiment 33, wherein thebuffer is histidine.

Embodiment 35: A composition according any of embodiments 1-34, whereinthe buffer has a pKa value ±1 pH unit from the target pH of thecomposition.

Embodiment 36: A composition according to any of embodiments 1 to 35,wherein a salt is present and the salt is selected from the groupconsisting of sodium chloride, magnesium chloride, sodium thiocyanate,ammonium thiocyanate, ammonium sulphate, ammonium chloride, calciumchloride, arginine hydrochloride, zinc chloride and sodium acetate orany combination thereof.

Embodiment 37: A composition according to embodiment 36, wherein thesalt is sodium chloride or magnesium chloride.

Embodiment 38: A composition according to embodiment 37, wherein thesalt is sodium chloride.

Embodiment 39: A composition according to embodiment 36, wherein thesalt is arginine-HCl.

Embodiment 40: A stable, liquid composition comprising an antibody andarginine, wherein the arginine is present in a concentration of between5 mM and 100 mM.

Embodiment 41: A composition according to embodiment 40, wherein thearginine is present in a concentration of between 5 mM and 50 mM.

Embodiment 42: A composition according to embodiment 41, wherein thearginine is present in a concentration of between 5 mM and 40 mM.

Embodiment 43: A composition according to embodiment 42, wherein thearginine is present in a concentration of between 5 mM and 35 mM.

Embodiment 44: A composition according to embodiment 43, wherein thearginine is present in a concentration of between 5 mM and 33 mM.

Embodiment 45: A composition according to embodiment 44, wherein thearginine is present in a concentration of between 5 mM and 30 mM.

Embodiment 46: A composition according to embodiment 45, wherein thearginine is present in a concentration of between 5 mM and 25 mM.

Embodiment 47: A composition according to embodiment 40 or embodiment41, wherein the arginine is present in a concentration of 50 mM, 40 mM,35 mM, 33 mM, 30 mM or 25 mM.

Embodiment 48: A composition according to any of embodiments 1 to 47,which has a pH of between 5.0 and 7.0.

Embodiment 49: A composition according to any of embodiments 1 to 48,which has a pH of 6.0 or 6.5.

Embodiment 50: A composition according to any of embodiments 1 to 49,which additionally comprises a surfactant.

Embodiment 51: A composition according to embodiment 50, wherein thesurfactant is polysorbate 80.

Embodiment 52: A composition according to embodiment 50 or embodiment51, wherein the surfactant is present within the composition in anamount of below 0.01%.

Embodiment 53: A composition according to any of embodiments 50 to 52,wherein the surfactant is present within the composition in an amount ofbelow 0.0075%.

Embodiment 54: A composition according to any of embodiments 50 to 52,wherein the surfactant is present within the composition in an amountbetween 0.001% and 0.005%.

Embodiment 55: A composition according to any of embodiments 50 to 54,wherein the surfactant is present within the composition in an amount of0.001%.

Embodiment 56: A composition according to any of embodiments 1 to 49,which does not comprise a surfactant.

Embodiment 57: A composition according to any of embodiments 1 to 56,which additionally comprises a tonicity modifying agent.

Embodiment 58: A composition according to embodiment 57, wherein thetonicity modifying agent is sucrose or mannitol.

Embodiment 59: A composition according to embodiment 58, wherein thetonicity modifying agent is sucrose.

Embodiment 60: A composition according to any of embodiments 57 to 59,wherein the tonicity modifying agent is present within the compositionin an amount of between 50 and 250 mM.

Embodiment 61: A composition according to any of embodiments 57 to 60,wherein the tonicity modifying agent is present within the compositionin an amount of between 100 and 200 mM.

Embodiment 62: A composition according to any of embodiments 57 to 61,wherein the tonicity modifying agent is present in an amount of 150 mM.

Embodiment 63: A composition according to any of embodiments 1 to 62,wherein the composition is pharmaceutically acceptable.

Embodiment 64: A composition according to any of embodiments 1 to 63,wherein the protein is an immunoglobulin.

Embodiment 65: A composition according to embodiment 64, wherein theprotein is an antibody.

Embodiment 66: A composition according to any of embodiments 1 to 65,wherein the protein is present within the composition in a concentrationof between 50 mg/ml and 300 mg/ml.

Embodiment 67: A composition according to embodiment 66, wherein theprotein is present within the composition in a concentration of between75 mg/ml and 300 mg/ml.

Embodiment 68: A composition according to embodiment 67, wherein theprotein is present within the composition in a concentration of between100 mg/ml and 300 mg/ml.

Embodiment 69: A composition according to embodiment 68, wherein theprotein is present within the composition in a concentration of between50 mg/ml and 200 mg/ml.

Embodiment 70: A composition according to embodiment 69, wherein theprotein is present within the composition in a concentration of 50, 55,60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, or 300 mg/ml.

Embodiment 71: A composition according to any of embodiments 1 to 70,which has a viscosity of 50 cP or less when measured at 25° C.

Embodiment 72: A composition according to embodiment 71, which has aviscosity of between 1 and 10 cP or less when measured at 25° C.

Embodiment 73: A composition according to embodiment 71 or embodiment72, which has a viscosity of between 2 and 10 cP or less when measuredat 25° C.

Embodiment 74: A composition according to embodiment 1, which comprises:

-   -   (a) ≧50 mg/ml of a protein, which is an antibody;    -   (b) 30 mM or lower of a salt, such as sodium chloride or        magnesium chloride;    -   (c) 50 mM or lower of a buffer such as histidine buffer;    -   (d) 0-25 mM of an amino acid, such as arginine or glycine;    -   (e) 0.001-0.005% of a non-ionic surfactant;    -   (f) 100-200 mM of a tonicity modifying agent, such as sucrose,        propylene glycol, glycerol, mannitol or D-sorbitol;        buffered to a pH of between 5 and 7.

Embodiment 75: A composition according to embodiment 1, which comprises:

-   -   (a) 100 mg/ml of a protein, which is an antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM sucrose;        buffered to a pH of between 5 and 7.

Embodiment 76: A composition according to embodiment 1, which comprises:

-   -   (a) 100 mg/ml of a protein, which is an antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM mannitol;        buffered to a pH of between 5 and 7.

Embodiment 77: A composition according to embodiment 1, which comprises:

-   -   (a) 100 mg/ml of a protein, which is an antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 0.001% polysorbate 80;    -   (f) 150 mM sucrose;        buffered to a pH of 6.5.

Embodiment 78: A composition according to embodiment 1, which comprises:

-   -   (a) 100 mg/ml of a protein, which is an antibody;    -   (b) 25 mM sodium chloride;    -   (c) 33 mM histidine buffer;    -   (d) 25 mM arginine;    -   (e) 150 mM sucrose;        Buffered to a pH between 5 and 7.

Embodiment 79: A composition according to any of the embodiments 1-78,wherein the composition is stable at room temperature.

Embodiment 80: A composition according to any of the embodiments 1-79,wherein the composition is stable at temperatures between 15 and 30° C.

Embodiment 81: A composition according to any of embodiments 1 to 80,wherein the protein is a monoclonal antibody.

Embodiment 82: A composition according to embodiment 65 or 81, whereinthe antibody is of the IgG4 subtype.

Embodiment 83: A composition according to embodiment 65, 81 or 82,wherein the monoclonal antibody is an anti-IL20 monoclonal antibody.

Embodiment 84: A composition according to embodiment 65, 81 or 82,wherein the monoclonal antibody is an anti-TFPI monoclonal antibody.

Embodiment 85: A composition according to embodiment 65, 81 or 82,wherein the monoclonal antibody is an anti-C5aR monoclonal antibody.

Embodiment 86: A composition according to embodiment 65, 81 or 82,wherein the monoclonal antibody is an anti-NKG2D monoclonal antibody.

Embodiment 87: A composition according to embodiment 65, 81 or 82,wherein the monoclonal antibody is an anti-NKG2A monoclonal antibody.

Embodiment 88: A stable protein composition according to any ofembodiments 1 to 87 for use in therapy.

Embodiment 89: A method of treating an inflammatory disease whichcomprises administering to a patient a therapeutically effective amountof a composition according to embodiment 83.

Embodiment 90: A composition according to embodiment 83 for use in thetreatment of an inflammatory disease.

Embodiment 91: Use of a composition according to embodiment 83 in themanufacture of a medicament for the treatment of an inflammatorydisease.

Embodiment 92: A pharmaceutical composition comprising an anti-IL20composition according to embodiment 83 for use in the treatment of aninflammatory disease.

Embodiment 93: A method of treating a coagulopathy which comprisesadministering to a patient a therapeutically effective amount of acomposition according to embodiment 84.

Embodiment 94: A composition according to embodiment 84 for use in thetreatment of a coagulopathy.

Embodiment 95: Use of a composition according to embodiment 84 in themanufacture of a medicament for the treatment of a coagulopathy.

Embodiment 96: A pharmaceutical composition comprising an anti-TFPIcomposition according to embodiment 84 for use in the treatment of acoagulopathy.

Embodiment 97: A method of treating an inflammatory disease whichcomprises administering to a patient a therapeutically effective amountof a composition according to embodiment 84.

Embodiment 98: A composition according to embodiment 85 for use in thetreatment of an inflammatory disease.

Embodiment 99: Use of a composition according to embodiment 85 in themanufacture of a medicament for the treatment of an inflammatorydisease.

Embodiment 100: A pharmaceutical composition comprising an anti-C5aRcomposition according to embodiment 85 for use in the treatment of aninflammatory disease.

Embodiment 101: A method of treating an inflammatory disease whichcomprises administering to a patient a therapeutically effective amountof a composition according to embodiment 86.

Embodiment 102: A composition according to embodiment 86 for use in thetreatment of an inflammatory disease.

Embodiment 103: Use of a composition according to embodiment 86 in themanufacture of a medicament for the treatment of an inflammatorydisease.

Embodiment 104: A pharmaceutical composition comprising an anti-NKG2Dcomposition according to embodiment 86 for use in the treatment of aninflammatory disease.

Embodiment 105: A method of treating an inflammatory disease whichcomprises administering to a patient a therapeutically effective amountof a composition according to embodiment 87.

Embodiment 106: A composition according to embodiment 87 for use in thetreatment of an inflammatory disease.

Embodiment 107: Use of a composition according to embodiment 87 in themanufacture of a medicament for the treatment of an inflammatorydisease.

Embodiment 108: A pharmaceutical composition comprising an anti-NKG2Acomposition according to embodiment 87 for use in the treatment of aninflammatory disease.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

Unless otherwise indicated, all exact values provided herein arerepresentative of corresponding approximate values (e.g., all exactexemplary values provided with respect to a particular factor ormeasurement can be considered to also provide a correspondingapproximate measurement, modified by “about,” where appropriate). When arange is given, the range includes both end values, unless otherwiseindicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

1. A stable, liquid composition comprising a protein, a salt and/or abuffer, characterised in that the total concentration of said saltand/or buffer is lower than 100 mM.
 2. A composition according to claim1, wherein the total concentration of said salt and/or a buffer is lowerthan 60 mM.
 3. A composition according to claim 1, which does notcomprise a surfactant.
 4. A composition according to claim 1, whereinthe protein is present within the composition in a concentration between100 mg/ml and 300 mg/ml.
 5. A composition according to claim 1, whereinthe composition is stable at room temperature.
 6. A compositionaccording to claim 1, which has a viscosity of 50 cP or less whenmeasured at 25° C.
 7. A stable, liquid composition comprising anantibody and arginine, wherein the arginine is present in aconcentration of between 5 mM and 100 mM.
 8. A stable, liquidcomposition according to claim 7, wherein the concentration of arginineis between 5mM and 30 mM.
 9. A composition according to claim 1, whereinthe protein is an antibody.
 10. A composition according to claim 9,wherein the antibody is of the IgG4 subtype.
 11. A composition accordingto claim 9, wherein the monoclonal antibody is selected from the groupconsisting of an anti-IL20 monoclonal antibody, an anti-C5aR monoclonalantibody, an anti-NKG2D monoclonal antibody and an anti-NKG2A monoclonalantibody.
 12. A composition according to claim 9, wherein the monoclonalantibody is an anti-TFPI monoclonal antibody.
 13. A method of treatingan inflammatory disease which comprises administering to a patient atherapeutically effective amount of a composition according to claim 11.14. A method of treating a coagulopathy which comprises administering toa patient a therapeutically effective amount of a composition accordingto claim 12.